Related Experiment Video

Updated: Jun 26, 2026

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
09:16

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

Published on: January 22, 2016

Mu-opioid receptor activation by methamphetamine metabolite 4-hydroxyamphetamine: a computational insight into a

Anushanga Amarasinghe Rodrigo1,2, Ranga Srinath Jayakody1,2

  • 1Center for Scientific Computing and Advanced Drug Discovery, University of Sri Jayewardenepura, Sri Lanka.

Journal of Biomolecular Structure & Dynamics
|June 24, 2026
PubMed

Insights

Methamphetamine metabolite 4-hydroxyamphetamine (4HAMP) may interact with the Mu opioid receptor (MOR), suggesting a potential role for the opioid system in methamphetamine addiction. Further research is needed to confirm these molecular findings.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Computational Chemistry

Background:

  • Methamphetamine addiction is a global health issue with unclear molecular underpinnings.
  • The interactions of methamphetamine and its metabolite 4-hydroxyamphetamine (4HAMP) with the Mu opioid receptor (MOR) are unknown.

Purpose of the Study:

  • To investigate the binding interactions and conformational effects of methamphetamine and 4HAMP on the MOR using computational methods.
  • To explore the potential involvement of the opioid system in methamphetamine addiction.

Main Methods:

  • Molecular docking
  • Molecular dynamics simulations (250 ns)
  • Principal component analysis
  • Free energy landscape mapping
  • MM/GBSA and adaptive biasing free energy (ABFE) calculations

Main Results:

  • Both methamphetamine and 4HAMP exhibited comparable docking and MM/GBSA binding scores.
  • ABFE calculations revealed a more favorable binding free energy for the 4HAMP:MOR complex compared to methamphetamine.
  • The 4HAMP:MOR complex was stabilized by key interactions including a salt bridge, hydrogen bonding, and van der Waals forces, associated with active-like receptor conformations.
  • The 4HAMP:MOR complex demonstrated stable conformational behavior during simulations.

Conclusions:

  • 4-hydroxyamphetamine (4HAMP) shows potential compatibility with the Mu opioid receptor (MOR) orthosteric site.
  • These findings propose a hypothesis of opioid system involvement in methamphetamine addiction, requiring experimental validation.
  • The study provides mechanistic insights into potential 4HAMP:MOR interactions.
Keywords:
4-hydroxyamphetamine (4HAMP)Mu opioid receptor (MOR)free energy calculationmethamphetaminemolecular dynamics simulationreceptor activation

More Related Videos

Single Cell Measurement of Dopamine Release with Simultaneous Voltage-clamp and Amperometry07:30

Single Cell Measurement of Dopamine Release with Simultaneous Voltage-clamp and Amperometry

Published on: November 21, 2012

Rodent Brain Microinjection to Study Molecular Substrates of Motivated Behavior10:05

Rodent Brain Microinjection to Study Molecular Substrates of Motivated Behavior

Published on: September 16, 2015

Related Concept Videos

Drug Abuse and Addiction: Pharmacological Phenomena01:15

Drug Abuse and Addiction: Pharmacological Phenomena

Drug dependence, abuse, and addiction are complex phenomena that can precipitate various abnormal states. Physical dependence refers to a state of pharmacological adaptation to a drug. This adaptation often results in tolerance—a reduced response to the drug after repeated administrations. When the drug use is abruptly stopped, withdrawal symptoms occur due to the body's need to readjust from the pharmacologically induced imbalance. However, tolerance and withdrawal symptoms do not necessarily...
Opioid Receptors: Overview01:22

Opioid Receptors: Overview

Opioid receptors, including the mu (μ, MOR), delta (δ, DOR), and kappa (κ, KOR) types, belong to the rhodopsin family of G protein-coupled receptors. These receptors are located throughout the central and peripheral nervous systems and in non-neuronal tissues such as macrophages and astrocytes. Opioid receptor ligands can be categorized into agonists or antagonists. Highly selective agonists include [d-Ala2, MePhe4, Gly(ol)5]-enkephalin or DAMGO for MOR, [D-Pen2, D-Pen5]-enkephalin or DPDPE for...
Opioid Analgesics: Synthetic and Semisynthetic Opioids01:15

Opioid Analgesics: Synthetic and Semisynthetic Opioids

Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
CNS Stimulants: Cocaine, Amphetamines and Cannabinoids01:24

CNS Stimulants: Cocaine, Amphetamines and Cannabinoids

CNS stimulants, such as cocaine, amphetamines, and cannabinoids, have varying structures and mechanisms of action that lead to different therapeutic effects and side effects. Cocaine, with its molecular formula C17H21NO4, is a tropane alkaloid and a tertiary amino compound. It has two chemical forms: the hydrochloride salt and the "freebase." The former is in powder form, while the latter involves removing the hydrochloride salt to create a form that can be smoked. Cocaine exerts its effects by...
Analgesia and Pain Management01:25

Analgesia and Pain Management

Pain is critical to various clinical pathologies, provoking an urgent need for effective management. Pain, whether acute or chronic, is a complex neurochemical process. Its alleviation depends on the type, with nonopioid analgesics effective for mild to moderate pain, such as musculoskeletal or inflammatory pain, while neuropathic pain responds best to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine reuptake inhibitors. For severe acute or chronic pain, opioids may be...
Adrenergic Agonists: Indirect-Acting Agents01:25

Adrenergic Agonists: Indirect-Acting Agents

Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...